Method for delivering dosage form for diltiazem

ABSTRACT

A device is disclosed for delivering diltiazem at a controlled and substantially zero order rate over a prolonged period of time.

This appln. is a cont. of U.S. pat. appln. Ser. No. 07/201,519 filed 2June 1988 now U.S. Pat. No. 4,859,470 issued Aug. 22, 1989. Appln. Ser.No. 07/201,519 is incorporated herein by reference and benefit isclaimed of its filing date. These applns. are assigned of record to ALZACorporation of Palo Alto, Calif.

FIELD OF THE INVENTION

This invention pertains to a dosage form comprising a member selectedfrom the group consisting of diltiazem and its pharmaceuticallyacceptable salts. The invention also concerns a method for administeringdiltiazem and its acceptable salts for treating angina.

BACKGROUND OF THE INVENTION

The drug diltiazem chemically is1,5-benzothiazepin-4(5H)one,3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl). Diltiazemis therapeutically indicated as a calcium ion influx inhibitor, whichactivity is known also as calcium channel blocker and as calciumantagonist.

The biological activity of diltiazem is its ability to inhibit theinflux of calcium ions during membrane depolarization of cardiac andvascular smooth muscles. The drug diltiazem and its pharmaceuticallyacceptable salts is a potent dilator of coronary arteries, bothepicardial and subendocardial. Diltiazem exhibits the ability toincrease exercise tolerance due to diltiazem's ability to reducemyocardial oxygen demand. This biological activity is effective by areduction in the heart rate and the systemic blood pressure insubmaximal and maximal exercise work loads. These activities indicatediltiazem is useful for the management of myocardial ischemia and anginadue to coronary artery spasm.

Presently diltiazem is administered by conventional non-rate controlledtablets in single doses of 30 to 120 milligrams taken three or fourtimes a day. This administration results in detectable plasma levelswithin about 30 to 60 minutes and peak levels in about two to threehours after diltiazem administration. The therapeutic level fordiltiazem is about 50 to 200 nanograms per milliliter of plasma, asreported in Physician's Desk Reference. 42nd Ed., pp 1221-22, (1988).

In the light of the above presentation, it will be appreciated by thoseversed in the pharmaceutical dispensing art, to which this inventionpertains, that a pressing need exists for a dosage form that deliversdiltiazem at a controlled rate to a patient in critical need ofcardiovascular diltiazem therapy. The pressing need exists also for anoral dosage form that delivers diltiazem at a controlled rate and at aconstant dose per unit time over a prolonged period of time. The needexists for a rate controlled dosage form for the gastrointestinaldelivery of diltiazem for obtaining diltiazem's beneficial hemodynamiceffects by a dosage form that is free of fluid wash-out of diltiazemfrom the dosage form and deliveres it at a controlled rate that issubstantially independent of the variable environment of thegastrointestinal tract. It will be appreciated further by those versedin the dispensing art that such a novel and unique dosage form that canadminister diltiazem at a rate controlled dose over time and,simultaneously, provide cardiovascular therapy would represent both anadvancement and a valuable improvement in the medical art.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide a dosage form for deliveringdiltiazem in a rate controlled amount and wherein the dosage formsubstantially overcomes the deficiencies associated with the prior art.

Another object of the present invention is to provide a dosage form foradministering diltiazem and it addition salts in a rate controlled doseof a prolonged period up to thirty hours for cardiovascular therapyincluding ischemia and angina pectoris.

Another object of the present invention is to provide a pharmaceuticaldosage form that makes available sustained and controlled diltiazemtherapeutic activity.

Another object of the invention is to provide a novel dosage formmanufactured as an osmotic device that can administer diltiazem to abiological receptor site to produce the desired pharmaceutical effect.

Another object of the present invention is to provide a dosage formmanufactured as an osmotic device that substantially reduces and/oreliminates the unwanted influences of the gastrointestinal tract, andwhich osmotic device still provides controlled administration ofdiltiazem over time.

Another object of the present invention is to provide a dosage formmanufactured as an osmotic device comprising a composition thatsubstantially reduces and/or eliminates fluid wash-out of diltiazemduring the drug delivery period of diltiazem and its salts.

Another object of the invention is to provide an osmotic device adaptedand sized for orally administering diltiazem, which dosage formcomprises a first composition comprising diltiazem and a contactingsecond composition that acts in harmony for the rate controlledadministration of diltiazem to the gastrointestinal tract of awarm-blooded animal.

Another object of this invention is to provide a complete pharmaceuticalregimen comprising a composition comprising diltiazem that can bedispensed from a dosage form, the use of which requires interventiononly for initiation and possible termination of the regimen.

Another object of this invention is to provide a method for treatingcardiovascular diseases by orally administering a member selected fromthe group consisting of diltiazem and its acceptable salts in a ratecontrolled dose per unit time to a warm-blooded animal, includinghumans, in need of cardiovascular therapy.

Other objects, features and advantages of this invention will be moreapparent to those versed in the dispensing art from the followingdetailed specification taken in conjunction with the drawings and theaccompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawings figuresare as follows:

FIG. 1 is a view of a dosage form made as an osmotic device shaped andsized for orally administering the beneficial drug diltiazem to thegastrointestinal tract over a prolonged period of time; and

FIG. 2a and 2b are a partially opened view of the dosage form of FIG. 1with a part of the wall of the dosage form removed for illustrating thestructure of the dosage form.

FIG. 3 is a graph that illustrates the rate of release of diltiazem fora device provided by the invention; and,

FIG. 4 is a graph that illustrates the cumulative amount of diltiazemreleased over 24 hours.

In the drawings and in the specification like parts in related figuresare identified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further described elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawing figures in detail, which drawing figures arean example of the dosage form provided by the invention and whichexample is not to be considered as limiting, one example of the osmoticdosage form is illustrated in FIG. 1 and in FIG. 2.

In FIG. 1, an osmotic dosage form is designated by the numeral 10.Dosage form 10 comprises a body member 11 comprising wall 12. Wall 12surrounds and defines an internal compartment not seen in FIG. 1. Dosageform 10 comprises at least one passageway 13 for connecting the interiorof dosage form 10 with the exterior environment of use.

In FIG. 2a, osmotic dosage form 10 is seen in opened view forillustrating the internal structure of dosage form 10. In FIG. 2a,dosage form 10 comprises body 11 and wall 12. Wall 12 surrounds anddefines an internal compartment 14. Wall 12 comprises at least onepassageway 13 or, optionally, more than one exit passageway, as seen inFIG. 2b, for dispensing a member selected from the group consisting ofdiltiazem 15 and its pharmaceutically acceptable salts in compartment 14from dosage form 10. The optionally preferred two passageways are usefulfor avoiding occasional blockage thereof by the gel comprising thediltiazem layer.

Wall 12 of dosage form 10 comprises a composition that is permeable tothe passage of an exterior fluid present in the environment of use, andit is substantially impermeable to the passage of diltiazem 15 and itssalts, and to other ingredients in compartment 14. Wall 12 issubstantially inert, and it maintains its physical and chemicalintegrity during the drug dispensing life of dosage form 10. The phrase,"keeps its physical and chemical integrity," means wall 12 does not loseits structure and it does not change during the dispensing life ofdosage form 10. Wall 12, in a presently preferred embodiment, comprisesa member selected from the group consisting of a cellulose ester, acellulose ether and a cellulose ester-ether. In a more preferredembodiment, wall 12 comprises a member selected from the groupconsisting of a cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, and ethyl cellulose. The polymeric members comprising wall12 comprise cellulose acetate having a degree of substitution up to 1and an acetyl content up to 21%, cellulose diacetate having a degree ofsubstitution of 1 to 2 and an acetyl content of 21% to 35%, cellulosetriacetate having a degree of substitution of 2 to 3 and an acetylcontent of 35% to 44%, and ethyl cellulose comprising an ethoxy groupdegree of substitution of 1.5 to 3, about 40% to 50% ethoxy content, anda viscosity range of 7 to 100 centipoises, or higher. The amount of acellulosic polymer in wall 12 of dosage form 10 is usually from 65weight percent (wt %) to 100 wt %. The polymers are known to the art inU. S. Pat. Nos. 3,845,770; 3,916,899 and in 4,160,020; and in Handbookof Common Polymers by J. R. Scott and W. J. Roff, (1971) published byCRC Press, Cleveland, Ohio.

Wall 12 of dosage form 10, optionally, comprises ahydroxypropylmethylcellulose flux enhancer for aiding in governing thefluid flux through wall 12 per unit time. Thehydroxypropvlmethvlcellulose used for the purpose of this inventionexhibits a molecular weight of about 9,200 to 16,000. The amount ofhydroxypropylmethylcellulose optionally present in wall 12 generallycomprises from 1 wt % to 15 wt %. Wall 12 comprises, optionally, apolyethylene glycol flux enhancer for aiding in governing fluid fluxthrough semipermeable wall 12. The polyethylene glycol comprises amolecular weight range of 1500 to 7500. The concentration ofpolyethylene in wall 12, optionally, comprises from 1 wt % to b 15 wt %.The total concentration of all ingredients in wall 12 is 100 wt %.

Internal compartment 24 comprises a member selected from the groupconsisting of diltiazem and its pharmaceutically acceptable salts 15.Representative of nontoxic, pharmaceutically acceptable salts ofdiltiazem comprise a member selected from the group consisting of thehydrochloride, hydrobromide, sulfate, phosphate, lactate, citrate,tartrate, malate, maleate, fumurate, ascorbate, gulconate, asparate,salicylate, and the like. Internal compartment 14 comprises diltiazemand its acid addition salts in an amount of from 30 mg to 500 mg, withpresently preferred individual dosage forms comprising 60 mg, 120 mg,180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 425 mg, and the like.

Diltiazem therapeutically acceptable salts are highly soluble in water,in artificial gastric fluid and in artificial intestinal fluid. Forexample, the solubility of diltiazem hydrochloride at 37° C. in water is612 mg/ml, in artificial gastric fluid it is 668 mg/ml, and inartificial intestinal fluid it is 611 mg/ml. This high solubilityleads-away from incorporating and delivering diltiazem by an osmoticdosage form in view of the prior art disclosure in J. PharmaceuticalSciences, Vol. 64, No. 12, pp 1987 to 1991, (1975). The referenceteaches that less than forty percent of diltiazem would be delivered ata zero order rate from an osmotic system. The mass of diltiazemdelivered is ascertained from the mass delivery zero order equation asfollows: ##EQU1## wherein m_(t) is the total mass of drug diltiazemcontained in the osmotic system, m_(z) is the mass of diltiazemdelivered at zero order, ρ is the density of the diltiazem core, and Sis the solubility of diltiazem.

This invention unexpectedly discovered diltiazem could have a massdelivered greater from an osmotic system greater than ninety percent byproviding the osmotic system with an unobvious diltiazem core. Thediltiazem core comprises from 70 wt % to 96 wt % of a member selectedfrom the group consisting of diltiazem and its acceptable salts; from0.5 wt % to 15 wt % of an acrylic acid polymer of the formula: ##STR1##wherein n is a positive number for providing an acrylic acid polymercomprising a molecular weight of 2,500,000 to 4,000,000; from 0.5 wt %to 20 wt % of a polymer of the formula ##STR2## wherein n is a positivewhole number for providing a polyethylene oxide comprising a molecularweight of 4,000,000 to 5,500,000: from 0.5 wt % to 20 wt % of apolyvinylpyrrolidone comprising a molecular weight of 35,000 to 40,000and from 0 wt % to 5 wt % of a member selected from the lubricantsconsisting of magnesium stearate and stearic acid, with the weight ofall ingredients comprising the diltiazem core equals to 100 wt %.

Dosage form 10 in compartment 14 comprises a push composition 16. Pushcomposition 16, when dosage form 10 is in operation in a fluidenvironment of use, pushes diltiazem core 15 from dosage form 10. Pushcomposition 16 comprises from 70 wt % to 95 wt % of a polyethylene oxidecomprising a molecular weight of about 6,200,000 to 7,500,000; from 1 wt% to 20 wt % of an osmagent selected from the group consisting of anosmotically active salt, carbohydrate, polysaccharide, oxide and acidsolute; from 1 wt % to 15 wt % of a hydroxypropylmethylcellulosecomprising a molecular weight of about 9,000 to 16,000; and from 0.0 wt% to 3 wt % of ferric oxide, with the weight of all ingredients in pushcomposition 16 equal to 100 wt %.

The expression, "exit passageway 13," comprises means and methodssuitable for dispensing the beneficial drug diltiazem 15 from dosageform 10. The exit means include at least one passageway that passesthrough wall 12 for communicating diltiazem in compartment 14 with theexterior of dosage form 10. The expression, "at least one passageway,"includes aperture, orifice, bore, pore, porous element through whichdiltiazem can be dispensed, a hollow fiber, capillary tube, microporousinsert, microporous overlay, and the like. Thus, a wall that is at leastin part microporous is optional with the invention. The expressionincludes a material that erodes or is leached from wall 12 in the fluidenvironment of use to produce at least one passageway of controlledreleasing dimensions. Representative materials suitable for forming atleast one passageway, two passageways, or more, include an erodiblepoly(glycolic) or poly(lactic) acid member in the wall, a gelatinousfilament, poly(vinyl alcohol), leachable materials such as fluidremovable pore formers providing exit pores of release rate controllingproperties, and the like. A passageway or a plurality of passageways canbe formed by leaching a material such as sorbitol from the wall. Thepassageway can have any shape such as round, triangular, square,elliptical, irregular, and the like. The dosage form can be constructedwith one or more passageways in a spaced apart relation on more than asingle distant surface of a dosage form. Passageways and equipment forforming passageways are disclosed in U. S. Pat. Nos. 3,916,889;4,063,064 and 4,088,864. Representative passageways formed by governedleaching to produce a pore of precontrolled size are disclosed in U. S.Pat. No. 4,200,098.

Dosage form 10 is manufactured by standard techniques. For example, inone manufacture diltiazem and the other ingredients comprising thediltiazem core are homogeneously blended and pressed into a solid core.The core possesses dimensions that correspond to the internal dimensionof the area occupied by core 15 in the dosage form 10. The core alsopossesses dimensions corresponding to the dimensions of the pushcomposition for forming a contacting surface arrangement therewith. Inthis manufacture, diltiazem and the other ingredients comprising thecore are blended with a solvent and mixed into a solid or semisolid formby conventional methods such as ballmilling, calendering, stirring orrollmilling and then pressed into a preselected shape. Next, the pushcomposition is placed in contact with the drug core. The drug core, pushcomposition can be placed in contacting arrangement by using aconventional two-layered press. The contacting drug core, pushcomposition are coated with a semipermeable wall. The wall can beapplied by compression coating, molding, spraying, dipping, or airsuspension procedures. The air suspension and the air tumblingprocedures comprise suspending and tumbling the pressed drug core, andthe push composition in a current of air containing the wall formingcomposition.

In another manufacture, dosage form 10 is manufactured by the wetgranulation technique. In the wet granulation technique, the diltiazemand the ingredients comprising the diltiazem composition are blendedusing an organic cosolvent, such as isopropyl alcohol-methylenedichloride 80/20 v/v (volume/volume) as the granulation fluid. Theingredients forming the diltiazem composition are passed through a 40mesh screen and thoroughly blended in a mixer. Other optionalingredients comprising the diltiazem composition are dissolved in aportion of the granulation fluid and added to the drug blend withcontinual mixing in the blender. The granulating fluid is added until ablend is produced, which wet blend is then forced through a 20 meshscreen onto oven trays. The blend is dried for 18 to 24 hours at 50° C.in a forced air oven. The dried granules are then sized through a 20mesh screen. Next, a lubricant such as magnesium stearate, which hasbeen passed through an 80 mesh screen, is added to the dry screenedgranules and blended in a V-blender for 5 to 10 minutes. The compositionis pressed into a layer, for example, in a 3-station Manesty® layerpress. The speed of the press is set at 30 rpm and the maximum load setat 2 tons. The diltiazem layer is pressed against the push compositionand the bilayer drug core fed to a coating machine.

Another manufacturing process that can be used for providing the drugcore, push composition comprises blending the powdered ingredientscomprising the drug core, or the push composition separately in a fluidbed granulator. After the powdered ingredients are dry blended in thegranulator, a granulating fluid, for example, poly(vinylpyrrolidone) inwater, is sprayed onto the powders. The coated powders then are dried inthe granulator. This process granulates all the ingredients presenttherein while adding the granulating fluid. After the granules are drieda lubricant, such as stearic acid or magnesium stearate is added to thegranules in a V-blender and blended 5 to 10 minutes. The granules thenare pressed in the manner described above.

DESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomemore apparent to those versed in the dispensing art in the light of thepresent disclosure, the drawing figures, and the accompanying claims.

EXAMPLE 1

A device for delivering diltiazem is made as follows: first, 9.40 kg ofdiltiazem hydrochloride, 0.10 kg of Carbomer®-934-P acrylic acid polymerhaving am molecular weight of about 3,000,000, and 0.20 kg ofpolyethylene oxide having a molecular weight of about 5,000,000 areadded to a blender and blended for 18 minutes to produce a uniform mix.Next 0.20 kg of polyvinylpyrrolidone having a molecular weight of about38,000 is mixed with 350 ml of anhydrous ethyl alcohol to form agranulation fluid. Then, the granulating fluid is added slowly to theblended ingredients, and all the ingredients blended to produce a wetmass. The wet mass is dried in a forced air oven for 17 to 23 hours atroom temperature, about 25° C., to evaporate the ethyl alcohol. Then,the dry granules are given an additional drying for 2 to 4 hours at 50°C. The dry granules are then passed through a 30 mesh screen. Next, 0.10kg of the lubricant magnesium stearate is added to the dry blend andblended for 9 minutes to produce a homogeneous composition. Thediltiazem composition is stored until a push composition is prepared formaking the final assembled device.

The push composition is made as follows: first, 4.35 kg of polyethyleneoxide having a 7,000,000 molecular weight, 0.35 kg of sodium chloride,and 0.25 kg of hydroxypropylmethylcellulose having a viscosity of 5centipoises are blended in a blender for 8.2 minutes to produce auniform blend. Next, 350 ml of denatured, anhydrous ethyl alcohol isadded as a granulating fluid to produce a wet mass. Next the granulatedwet mass is passed through a 30 mesh screen to form wet granules. Thewet granules next are spread onto trays and the wet granules dried atroom temperature of 25° C. for 20 to 25 hours. The dry granules then arepassed through a 20 mesh screen. The push composition now is ready formanufacturing the final device.

The granules comprising the diltiazem compositions are transferred tothe number one feed of a hopper and the granules comprising the pushcomposition are fed to the number two feed of a hopper. The feed hoppersare placed onto a bi-layer press and the diltiazem composition pressedonto the push composition.

Next, the pressed compositions are surrounded with a semipermeable wall.The wall forming composition is prepared as follows: first, a cosolventis prepared by mixing 80 parts of methylene chloride with 20 parts ofmethanol (wt/wt) and cellulose acetate having an acetyl content of 39.8%slowly added thereto. Then, hydroxypropylmethylcellulose having a 11,300molecular weight is added to the cosolvent with stirring followed by theaddition of polyethylene glycol having a 3350 molecular weight. The wallforming ingredients dissolved in the cosolvent to produce a cosolventcomprising 80% cellulose acetate, 10% hydroxypropylmethylcellulose, and10% polyethylene glycol, to obtain 3% solids. The pressed compositionsare placed in a coating unit, and the pressed compositions coated with asemipermeable wall.

Next the wall coated compositions are removed from the coater and anexit port is drilled through the wall by a laser. The dosage forms arethen dried in a humidity over at 50% RH and 50° C. for 48 hours toremove all residual solvent. The dosage forms are sized and shaped fororal admittance into the gastrointestinal tract of a human.

The device provided by this manufacture comprises a diltiazem dose of360 mg. The diltiazem composition comprises 94 wt % diltiazem, 1 wt %acrylic acid polymer, 2 wt % of polyethylene oxide coagulant 5,000,000molecular weight, 2 wt % polyvinylpyrrolidone, and 1 wt % magnesiumstearate. The push composition weighed 135 mg and comprises 87 wt %polyethylene oxide molecular weight 7,000,000, 7 wt % sodium chloride, 5wt % hydroxypropylmethylcellulose and 1 wt % ferric oxide. Thesemipermeable wall comprises 80 wt % cellulose acetate, 10 wt %polyethylene glycol and 10 wt % hydroxypropylmethylcellulose. The devicedelivers diltiazem for 24 hour at an average delivery rate of 15.3mg/hr.

EXAMPLE 2

The procedure of Example 1 is followed to provide a device comprisingthe following: a diltiazem composition comprising 240 ml dose ofdiltiazem with a 10 % over does in the composition, 2.81 mg of acrylicacid polymer having a 3,000,000 molecular weight, 5.62 mg ofpoly(ethylene oxidel coagulant having a 5,000,000 molecular weight, 5.62mg of poly(vinylpyrrolidone) having a 38,000 molecular weight, and 2.81mg of magnesium stearate; a push composition comprising 80.25 mg ofpoly(ethylene oxide) 303 having a 7,000,000 molecular weight, 6.46 mg ofsodium chloride, 4.61 mg of hydroxypropylmethylcellulose having a 9,200molecular weight, and 0.92 mg of ferric oxide; and a semipermeable wallweighing 22.20 mg comprising 80% cellulose acetate having a 39.8% acetylcontent, 10% hydroxypropylmethylcellulose having a 11,200 molecularweight and 10% polyethylene glycol having a 3350 molecular weight. Thedevice comprises two 15 mil passageways and exhibits the rate of releasein milligrams per hour as seen in FIG. 3.

EXAMPLE 3

The procedure described above is followed to provide a delivery devicecomprising: a diltiazem composition weighing 280 mg and comprising 94%diltiazem hydrochloride, 1 % polyacrylic acid with a 3,000,000 molecularweight, 2% Povidone® poly(vinylpyrrolidone) with a 38,000 molecularweight, and 1% stearic acid; a push composition weighing 90 mg andcomprising 87% Polyox®303 with a 7,500,000 molecular weight, 7% sodiumchloride, 5% hydroxypropylmethylcellulose with a 11,200 molecularweight, and 1% ferric oxide; and a semipermeable wall weighing 21.20 mgand comprising 80% cellulose acetate comprising a 39.8% acetyl content,10% polyethylene glycol having a 3350 molecular weight, and 10%hydroxypropylmethylcellulose having a 11,200 molecular weight. Thedevice comprises a pair of 15 mil exit ports and a means release rate of10.2 mg/hr. The cumulative amount of diltiazem hydrochloride release isseen in FIG. 4.

EXAMPLE 4

The example pertains to a method for delivering a member selected fromthe group consisting of diltiazem and its pharmaceutically acceptablesalts to a human patient in need of diltiazem and its salts, whichmethod comprises:

(a) admitting orally into the human a device comprising:

(1) a wall comprising a semipermeable composition, said wall surroundingand defining a compartment, which compartment comprises:

(A) a diltiazem composition comprising from 70 wt % to 96 wt % of amember selected from the group consisting of diltiazem and itspharmaceutically acceptable salts, from 0.5 wt % to 15 wt % ofpolyacrylic acid comprising a 2,500,000 to 4,000,000 molecular weight,from 0 5 wt % to 20 wt % of a poly(ethylene oxide) comprising a4,000,000 to 5,500,000 molecular weight, and from 0.5 wt % to 20 wt % ofa poly(vinylpyrrolidone) comprising a 35,000 to 40,000 molecular weight.

(B) a push composition comprising from 70 wt % to 95 wt % ofpoly(ethylene oxide) comprising a 6,200,000 to 7,500,000 molecularweight, from 1 wt % to 15 wt % of a hydroxypropylmethylcellulosecomprising a molecular weight of about 9,000 to 16,000;

(2) at least one passageway in the wall for delivering the memberselected from the group consisting of diltiazem and it salts from thedevice, said passageway comprising a cross section of 0.25 mm to 0.64mm; and,

(b) delivering diltiazem and its salts by the device imbibing fluidthrough the wall into the compartment to cause the diltiazem compositionto form a dispensable composition and to cause the push composition topush the diltiazem composition through the passageway, which diltiazemor a diltiazem salt is administered to the human in need thereof.

In summary, it will be appreciated the present invention contributes tothe diltiazem art an unobvious dosage form that possesses practicalmedical utility. While the invention has been described and pointed outin detail with reference to operative embodiments thereof, it will beunderstood that those skilled in the art will appreciate that variouschanges, modification, substitutions and omissions can be made withoutdeparting from the spirit of the invention. It is intended, therefore,that the invention embraces those equivalents within the scope of theclaims.

We claim:
 1. A method for delivering diltiazem to a recipient in needthereof, which method comprises:(a) admitting orally into the recipienta device comprising:(1) a wall surrounding and forming a compartment,which compartment comprises:(A) a diltiazem composition comprising from70 wt % to 96 wt % of a member selected from the group consisting ofdiltiazem and its pharmaceutically acceptable salts, from 0.5 wt % to 15wt % of polyacrylic acid comprising a 2,500,000 to 4,000,000 molecularweight, from 0.5 wt % to 20 wt % of a poly(ethylene oxide) comprising a4,000,000 to 5,500,000 molecular weight, and from 0.5 wt % to 20 wt % ofa poly(vinyl pyrrolidone) comprising a 35,000 to 40,000 molecularweight; (B) a push composition comprising from 70 wt % to 95 wt % ofpoly(ethylene oxide) comprising a 6,200,000 to 7,500,000 molecularweight, from 1 wt % to 20 wt % of an osmagent, and from 1 wt % to 15 wt% of a hydroxypropylmethylcellulose comprising a 9,000 to 16,000molecular weight; (2) at least one passageway in the wall; and, (b)delivering diltiazem by the device imbibing fluid through the wall intothe compartment to cause the diltiazem composition to form a dispensablecomposition and to cause the push composition to push the diltiazemcomposition through the passageway for delivering diltiazem to therecipient.
 2. A method for delivering diltiazem to a recipient in needthereof, which method comprises:(a) admitting orally into the recipienta dosage form comprising:(1) a wall comprising at least in part acomposition, which composition comprises a member selected from thegroup consisting of a cellulose ester, cellulose ether, celluloseester-ether, cellulose acylate, cellulose diacylate, cellulose acetate,cellulose diacetate and cellulose triacetate, which wall surrounds; (2)a compartment; (3) an osmotic core in the compartment, which corecomprises from 30 mg to 500 mg of a member selected from the groupconsisting of diltiazem and its pharmaceutically acceptable salts,wherein the salt is a member selected from the group consisting ofhydrochloride, hydrobromide, sulfate, phosphate, lactate, citrate,tartrate, malate, maleate, fumarate, ascorbate, gluconate, aspartatate,and salicylate; (4) means in the wall for delivering diltiazem from thedosage form, said means comprising a leached passageway formed in thewall when the dosage form is in the recipient, and, (b) delivering fromthe osmotic core from 30 mg up to 500 mg of diltiazem through theleached passageway to the recipient over 24 hours.
 3. The method fordelivering diltiazem to the recipient in need thereof according to claim1, wherein the leached passageway is replaced by an erodible diltiazemrelease rate controlling pore.
 4. The method for delivering diltiazem tothe recipient in need thereof according to claim 1, wherein the leachedpassageway is replaced by a drilled passageway.
 5. The method fordelivering diltiazem to the recipient in need thereof according to claim1, wherein the recipient comprises a gastrointestinal fluid and thediltiazem exhibits solubility in gastric and intestinal fluid.